Hydrosoluble pharmaceutical compositions containing salts of (-)cis-1,2-epoxypropylphosphonic acid with aminoacids

ABSTRACT

Hydrosoluble pharmaceutical compositions containing, as the active principal, salts of (-)cis-1,2-epoxypropylphosphonic acid with aminoacids such as arginine, ornithine, lysine, cysteine, and the like, characterized by containing a hydrophyllic organic base.

The present invention refers to pharmaceutical compositions havingantibiotic activity, which can be administered by the parenteral routein the form of a solution.

In the Italian Patent Applications Nos. 41002 A/78 and 26304 A/78 saltshaving formula I are described ##STR1## wherein A is an aminoacid, suchas lysine, arginine, ornithine, cysteine, methionine, glycine, choline,alanine, betaine, etc. whereas the anionic moiety is provided by(-)cis-1,2-epoxypropylphosphonic acid, compound known also asphosphomycin and used in human and veterinary therapy because of itsantibiotic properties.

Particularly, the phosphomycin arginine salt proved to be endowed withunexpected and advantageous therapeutic properties.

The compounds I, according to the processes described in said patentapplications, are prepared by reacting substantially equimolar amountsof (-)cis-1,2-epoxypropylphosphonic acid and of aminoacid, preferably inaqueous solution, or in hydroalcoholic solution with methyl or ethylalcohol.

The compounds so obtained proved, however, to be not very soluble, so asto make problematic their parenteral administration (especiallyendovenous) in form of solutions. On the other hand, said administrationroutes are very frequent in the clinical practice for antibiotictherapies.

It has now been found that compounds I, and namely the compound Iwherein A represents arginine, can be suitably formulated inhydrosoluble compositions, having a water solubility ranging from 10 and20% w/v, by adding a suitable amount of hydrophilic organic bases eitherduring the preparation of said salts or directly before the finalconditioning in pharmaceutical forms.

The base is preferably added in a molar ratio ranging from about 0.4 toabout 0.8, and even more preferably about 0.6.

Preferred hydropholic organic bases are 1,1-dimethyl-2-aminoethanol,2-aminobutanol, 2-amino-2-hydroxymethyl-1,3-propandiol and, generally,similar compounds belonging to the class of the aminoalcohols.

The pH of the solutions obtained according to the invention are in therange of physiologically acceptable values, namely from about 6.9 to7.4.

As already mentioned, the phosphomycin formulations according to thepresent invention, obtained by salification with aminoacids and with theabove organic bases, belonging to the class of the aminoalcohols, arecharacterized by a high water solubility, higher than that of similarsalts, and by the possibility to obtain, even by the oraladministration, higher and more prolonged blood levels of the antibioticin its active form.

Moreover, the compositions according to the invention--in comparisonwith other phosphomycin salts--exhibit an higher tropism for someorgans, such as lungs and kidneys.

On the other hand, the favourable toxicological characteristics ofphosphomycin as well as its wide antibacterial spectrum are not in anyway compromised.

The injectable pharmaceutical preparations according to the presentinvention may comprise obviously other suitable excipients, whose use isconventional and well known to the persons skilled in the art: similarlyknown are the sterility, apirogenicity and isotonicity conditions whichmust be met by said compositions for the foreseen use.

According to the invention, it is also possible to prepare liquid oralpharmaceutical compositions such as syrups, drinkable solutions,effervescent powders etc.

In the case of parenteral administration, the compositions of theinvention will contain from 0.1 to 0.5 g of the active principle, andfrom 0.5 to 1 g of the active principle in the case of oraladministration.

The daily posology will depend, of course, on the diagnosis, thepatient's gravity, age and weight.

In the following table, reported by way of non-limitative example, thehydrosoluble organic bases used in the respective amounts and theobtained solubility and pH results are reported.

                  TABLE                                                           ______________________________________                                        Compositions containing phosphomycin arginine salt (1:1)                      with hydrophilic organic bases.                                                                         Solubility                                          Organic base  Molar ratio g %      pH                                         ______________________________________                                         ##STR2##     0.5         18       6.9                                         ##STR3##     0.56        15       6.82                                        ##STR4##     0.55        14       6.93                                       ______________________________________                                    

I claim:
 1. A pharmaceutical composition having antibiotic propertiescomprising a salt of (-)cis-1,2-epoxypropylphosphonic acid with argininetogether with an aminoalcohol selected from the group consisting of1,1-dimethyl-2-aminoethanol, 2-aminobutanol and2-amino-2-hydroxymethyl-1,3-propandiol in a molar ratio of 0.4-0.8 toincrease the water solubility of said salt.
 2. A composition accordingto claim 1 in which the amino-alcohol is present in a molar ratio ofabout 0.6.